TY - JOUR
T1 - Roles of the BRD4 short isoform in phase separation and active gene transcription
AU - Han, Xinye
AU - Yu, Di
AU - Gu, Ruirui
AU - Jia, Yanjie
AU - Wang, Qi
AU - Jaganathan, Anbalagan
AU - Yang, Xuelan
AU - Yu, Miaomiao
AU - Babault, Nicolas
AU - Zhao, Chengcheng
AU - Yi, Huanfa
AU - Zhang, Qiang
AU - Zhou, Ming Ming
AU - Zeng, Lei
N1 - Funding Information:
We thank C.-M. Chiang of UT Southwestern Medical Center for providing valuable BRD4S-specific antibody and BRD4 mutant plasmids, S. Fu of the First Hospital at Jilin University for cancer cell lines, R.G. Roeder of Rockefeller University for helpful discussion and F. Wang and J. Zhang for assistance with microscopy. We thank the State Key Laboratory of Supramolecular Structure and Materials at Jilin University for the use of their research facilities. This work was supported in part by the research fund from the First Hospital of Jilin University (Changchun, China); the Open Project of the State Key Laboratory for Supramolecular Structure and Materials, JLU (grant no. SKLSSM201602); the JLU Science and Technology Innovative Research Team (grant no. JLUSTIRT, grant no. 2017TD-25); the International Center of Future Science, JLU; and the National Natural Science Foundation of China (grant no. 31770780; L.Z.).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - BRD4, a major tandem-bromodomain-containing transcription regulator, has two isoforms. The long isoform (BRD4L) has an extended C terminus that binds transcription cofactors, while the short isoform (BRD4S) lacks this C-terminal extension. Unlike BRD4L, the role of BRD4S in gene transcription remains unclear. Here, we report that, in human cancer cells, BRD4S forms nuclear puncta that possess liquid-like properties and that colocalize with BRD4L, MED1 and sites of histone H3 lysine 27 acetylation. BRD4 puncta are correlated with BRD4S but not BRD4L expression levels. BRD4S knockdown reduces BRD4S condensation, and ectopic expression promotes puncta formation and target gene transcription. BRD4S nuclear condensation is mediated by its intrinsically disordered regions and binding of its bromodomains to DNA and acetylated chromatin, respectively, and BRD4S phosphorylation diminishes BRD4 condensation. Our study illuminates a previously unappreciated role of BRD4S in organizing chromatin and transcription factors through phase separation to sustain gene transcription in chromatin for cancer cell proliferation.
AB - BRD4, a major tandem-bromodomain-containing transcription regulator, has two isoforms. The long isoform (BRD4L) has an extended C terminus that binds transcription cofactors, while the short isoform (BRD4S) lacks this C-terminal extension. Unlike BRD4L, the role of BRD4S in gene transcription remains unclear. Here, we report that, in human cancer cells, BRD4S forms nuclear puncta that possess liquid-like properties and that colocalize with BRD4L, MED1 and sites of histone H3 lysine 27 acetylation. BRD4 puncta are correlated with BRD4S but not BRD4L expression levels. BRD4S knockdown reduces BRD4S condensation, and ectopic expression promotes puncta formation and target gene transcription. BRD4S nuclear condensation is mediated by its intrinsically disordered regions and binding of its bromodomains to DNA and acetylated chromatin, respectively, and BRD4S phosphorylation diminishes BRD4 condensation. Our study illuminates a previously unappreciated role of BRD4S in organizing chromatin and transcription factors through phase separation to sustain gene transcription in chromatin for cancer cell proliferation.
UR - http://www.scopus.com/inward/record.url?scp=85081934570&partnerID=8YFLogxK
U2 - 10.1038/s41594-020-0394-8
DO - 10.1038/s41594-020-0394-8
M3 - Article
C2 - 32203489
AN - SCOPUS:85081934570
VL - 27
SP - 333
EP - 341
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 4
ER -